Packed bed chromatography processes play an important role in the production of biologic drug products. Many active biologics, such as proteins, are purified for use in drug products using packed bed chromatography. Chromatography column operation therefore may have a significant effect on manufacturing critical process parameters (CPP) and critical quality attributes (CQA). Moreover, the complexity and size of biologics, as compared to, e.g., small molecules, can make analyzing biologic quality and purity relatively more difficult. Thus, monitoring the quality, consistency, and integrity of chromatography processes and equipment via in-process controls is important to ensure that product quality meets any applicable standards (e.g., government regulations).
Generally, column integrity can be determined by the uniform plug flow of a mobile phase through a column's stationary phase (e.g., resin). Examples of loss of column integrity can include, for example, evidence of channeling, headspace, fouled areas of flow, and the like. Channeling may result when, among other things, a mobile phase is able to travel some distance from a column inlet towards the column's outlet without contacting the stationary phase. Headspace may refer to, among other things, when a lateral zone is created in a column that allows for non-plug flow of the mobile phase. Fouled areas of flow may include dirt or other residue on inlet or outlet frit surfaces, or on resin pores.
Several techniques exist for monitoring chromatography column performance and integrity. Some techniques, such as the pulse injection method for measuring height equivalent of a theoretical plate (HETP), require buffer solutions needing special preparation. Pulse injection techniques generally require operation of chromatography equipment and the column outside of normal processes, resulting in increased process time and labor. Other techniques include monitoring critical parameters (e.g., step yield, pre-pool volume, and maximum optical density during load) as a part of routine production. However, setting alarm limits on these parameters is difficult and imprecise, and may result in false alarms or overly broad limits.
There exists a need for methods, systems, and processes for measuring and managing column performance and integrity with accuracy and precision, and with minimal disruption to processes. Moreover, because of inherent differences between chromatography columns, chromatography column cycles, and/or production lots for any given product undergoing chromatography, there exists a need for methods, systems, and processes with which to customize analyses of column performance and integrity for a particular column or columns, a particular cycle or cycles, and/or a particular lot or lots of a product. Finally, there exists a need for precise in-process controls that use such analyses, and for methods and systems for responding to deviations from such controls, so that issues with column integrity and performance may be identified and corrected early, with minimal waste and expense.